Abstract
BackgroundThe prevalence of invasive fungal infections (IFIs) has increased steadily worldwide in the last few decades. Particularly, there has been a global rise in the number of infections among immunosuppressed people. These patients present severe clinical forms of the infections, which are commonly fatal, and they are more susceptible to opportunistic fungal infections than non-immunocompromised people. IFIs have historically been associated with high morbidity and mortality, partly because of the limitations of available antifungal therapies, including side effects, toxicities, drug interactions and antifungal resistance. Thus, the search for alternative therapies and/or the development of more specific drugs is a challenge that needs to be met. Genomics has created new ways of examining genes, which open new strategies for drug development and control of human diseases.ResultsIn silico analyses and manual mining selected initially 57 potential drug targets, based on 55 genes experimentally confirmed as essential for Candida albicans or Aspergillus fumigatus and other 2 genes (kre2 and erg6) relevant for fungal survival within the host. Orthologs for those 57 potential targets were also identified in eight human fungal pathogens (C. albicans, A. fumigatus, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Paracoccidioides lutzii, Coccidioides immitis, Cryptococcus neoformans and Histoplasma capsulatum). Of those, 10 genes were present in all pathogenic fungi analyzed and absent in the human genome. We focused on four candidates: trr1 that encodes for thioredoxin reductase, rim8 that encodes for a protein involved in the proteolytic activation of a transcriptional factor in response to alkaline pH, kre2 that encodes for α-1,2-mannosyltransferase and erg6 that encodes for Δ(24)-sterol C-methyltransferase.ConclusionsOur data show that the comparative genomics analysis of eight fungal pathogens enabled the identification of four new potential drug targets. The preferred profile for fungal targets includes proteins conserved among fungi, but absent in the human genome. These characteristics potentially minimize toxic side effects exerted by pharmacological inhibition of the cellular targets. From this first step of post-genomic analysis, we obtained information relevant to future new drug development.
Highlights
Introduction to cheminformatics in drug discoveryA personal view
The alignments of those 57 sequences against the genome of the 8 pathogenic fungi P. lutzii, P. brasiliensis isolates (Pb18 e Pb3), A. fumigatus, B. dermatitidis, C. albicans, C. immitis, C. neoformans, H. capsulatum confirmed the presence of all the genes (Additional file 1)
We reported a comparative genomic strategy to provide a list of potential antifungal drug targets for the human pathogenic fungi P. brasiliensis, P. lutzii, A. fumigatus, B. dermatitidis, C. albicans, C. immitis, C. neoformans and H. capsulatum
Summary
Introduction to cheminformatics in drug discoveryA personal view. In Chemioinformatics in drug discovery. The emergence of less common, but medically important, fungi has increased, especially in the large populations of immunocompromised patients and of those hospitalized with serious underlying diseases [1,2] These patients develop more severe clinical forms of mycoses, which are commonly fatal, and they are more susceptible to infections complex, amphotericin B cholesteryl sulfate and liposomal amphotericin B) have been developed and approved by the Food and Drug Administration (FDA). The azoles antifungals have many drug-drug interactions with multiple drug classes owing to their interference with hepatic cytochrome P450 enzymes [6] Another problem with azoles therapy is the acquired resistance of many pathogens to these drugs, which is the most common cause of refractory infection. The search for more specific drugs, in an effort to overcome the global problem of resistance to antifungal agents and minimize the serious side effects, is increasingly relevant and necessary
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